Does atrial fibrillation in elderly patients
with chronic heart failure limit the efficacy
of carvedilol? Suggestions from
an observational study

Cristina Opasich, Stefania De Feo, Giovanni Cioffi*, Giovanni Pulignano**,Donatella Del Sindaco§, Luigi Tarantini§§, Alessandra Gualco, Anna Patrignani Department of Cardiology, S. Maugeri Foundation, Institute of Care and Scientific Research, Pavia, *Departmentof Cardiology, Villa Bianca Hospital, Trento, **Department of Cardiology, San Camillo Hospital, Rome, §Departmentof Cardiology, INRCA, Institute of Care and Scientific Research, Rome, §§Department of Cardiology, San MartinoHospital, Belluno, Italy Background. No clinical investigation provided any information about a possible influence of atri-
Atrial fibrillation;
al fibrillation on the response to beta-blocker therapy in elderly patients with chronic heart failure
Carvedilol; Elderly;
(CHF). The aim of this study was to observe carvedilol effects in a cohort of patients > 70 years of age
Heart failure.
with CHF due to left ventricular dysfunction and with chronic atrial fibrillation.
Methods. An observational, 12-month prospective clinical and echocardiographic study was car-
ried out on 240 patients > 70 years of age with heart failure due to systolic dysfunction, 64 of whom
with atrial fibrillation.

Results. After 1 year of beta-blocker treatment, patients with atrial fibrillation and those in sinus
rhythm showed similar benefits, in terms of symptomatic improvement (NYHA -0.44 if atrial fib-
rillation vs -0.57 if sinus rhythm, p = NS), reduction of events (death + hospitalizations -38 vs -15%),
recovery of cardiac function (left ventricular ejection fraction
+8.8 vs +9.4%, p = NS; left ventric-
ular end-diastolic volume
-17.2 vs -12.5 ml, p = NS), and reduction in mitral regurgitation (-042
vs -0.57, p = NS). No difference was found between the two study groups regarding left ventricular
end-diastolic volume reduction (12% in atrial fibrillation patients and 18% in sinus rhythm patients,
p = NS) and prevalence of the “reverse remodeling” phenomenon (22 and 21%, respectively, p = NS).

Conclusions. In CHF patients > 70 years of age, beta-adrenergic blockade was shown to be equal-
ly effective in improving symptoms and left ventricular geometry and function in patients with atri-
al fibrillation or in sinus rhythm, without any adjunctive sign of long-term clinical deterioration.

atrial fibrillation17,18. However, the mean useful in patients with chronic heart failure age of patients involved in these studies (CHF), in that they improve left ventricular was 60 years, thus data on elderly CHF pa- function and reduce deaths from heart fail- tients with atrial fibrillation are lacking.
ure and hospital admissions1-4. These fa- vorable effects have recently been observed to evaluate the effects of carvedilol therapy even in elderly CHF patients5, who are sub- on the clinical status and left ventricular re- jects of a recently concluded, not yet pub- > 70 years of age with CHF due to left ven- Divisione di CardiologiaFondazione S. Maugeri Atrial fibrillation is present in about a tricular dysfunction and with chronic atrial quarter of CHF patients7-12 and seems to be 27100 PaviaE-mail: copasich@fsm.it a risk factor for significant morbidity13-16.
Retrospective analysis of the US Car-vedilol Trial and other studies showed that the benefits of beta-blockers seen in ran-domized trials (improvement of left ven- tricular ejection fraction [LVEF], physical (151 males, 89 females, mean age 76 ± 5.7 years, range 70-99 years) with an echocar- capacity, and, probably, reduction in the recruited by four heart failure clinics into a 12-month prospective study and their data collected in- dictors of clinical improvement and left ventricular re- to a single database. Sixty-four patients had permanent verse remodeling. Statistical significance was set at p chronic atrial fibrillation (27%), 24 of whom were fe- males. Thirty-nine out of the 64 patients were treatedwith carvedilol, while 25 subjects had contraindica-tions to such treatment. In fact, chronic obstructive pul- monary disease limited the carvedilol prescription in 12cases, low heart rate or blood pressure in 10 cases, and The clinical characteristics of all patients and com- severe peripheral arteriopathy in 3 cases. parisons between patients with atrial fibrillation and in Carvedilol was used together with angiotensin-con- verting enzyme inhibitors or sartans, spironolactone and Valvular disease was more frequent among patients digoxin (if not contraindicated) and started at a low dose of 3.125 mg twice daily and then progressively doubled Contraindications to carvedilol were present in sim- in order to reach the target dosage of 50 mg/day or symp- ilar percentages among patients with atrial fibrillation toms and signs indicative of “effective” beta-blockade (39%) and among those in sinus rhythm (31%). In the (defined as clinical stability on fixed diuretic dosage, latter group, chronic obstructive pulmonary disease heart rate and systolic blood pressure comprised between represented the main contraindication in 28, bradycar- 60-70 b/min and 100-120 mmHg, respectively). Four pa- dia or hypotension in 15, and peripheral vascular dis- tients were intolerant to carvedilol (worsening heart fail- ease (with or without diabetes) in 11 patients.
ure in 2, severe bradycardia in 2). Six patients died be- There were no differences in the tested characteris- fore the completion of the follow-up period (1 on and 5 tics between atrial fibrillation patients treated or not by off carvedilol therapy). Thus, clinical effects of 1 year of carvedilol. The same was true for sinus rhythm pa- carvedilol therapy in elderly patients with atrial fibrilla- tients. Moreover, apart from a slightly higher LVEF tion were assessed in 34 patients and compared with and, obviously, their heart rhythm, atrial fibrillation pa- those in patients without atrial fibrillation. Clinical and tients treated with carvedilol did not differ from sinus echocardiographic variables were recorded before and rhythm patients. As regards concomitant treatment, as after 12 months of carvedilol therapy in all survivors.
expected digoxin was more often prescribed in atrial Standard transthoracic echocardiographic studies were fibrillation patients. Dosages of furosemide were high- systematically performed by expert cardiologists at er among patients not treated with carvedilol, especial- baseline and at the end of the follow-up using a Megas Esaote Biomedica machine (Florence, Italy) equipped After 1 year of beta-blocker treatment, patients with with a 2.5 to 3.5 MHz annular-array transducer. Left ven- atrial fibrillation and those in sinus rhythm showed tricular volumes and LVEF were computed from apical similar benefits, in terms of symptomatic improvement 2- and 4-chamber views by the area-length method and and recovery of cardiac function (Table II). Of note, the mitral regurgitation was diagnosed by color Doppler and dose of carvedilol was significantly higher in atrial fib- quantified using a 1-4+ grading system. Details of the re- rillation patients (perhaps because of the ventricular re- producibility of echocardiographic measurements de- sponse control) but the dosages of furosemide had not tected in patients with heart failure from our laboratory been increased further. The portion of atrial fibrillation patients who could be defined “improved” at the final In this study we used the NYHA functional classifi- 1-year evaluation was 22%. This behavior was recog- cation as measure of the functional status, and the left nized in a similar percentage of counterparts with sinus ventricular end-diastolic volume (LVEDV), LVEF rhythm (28%, p = NS). Compared to the latter, our el- (normal if ≥ 50%) and the degree of mitral regurgitation ders with atrial fibrillation had a similar relevant de- as markers of the left ventricular remodeling process.
crease of the degree of mitral regurgitation over time Patients were defined as “improved” when a reduction (Table II). Concordantly, no difference was found be- of at least one NYHA functional class associated with tween the two study groups in terms of LVEDV reduc- an increase in LVEF > 10 points % were documented tion and prevalence of the reverse remodeling phenom- from baseline to 1-year evaluation. The left ventricular enon (22 and 21%, respectively, p = NS).
reverse remodeling phenomenon was recognized in At a multivariate analysis where atrial rhythm to- case LVEDV decreased > 24 ml/m2 from baseline to the gether with age, sex, Charlson score, systolic blood end of follow-up (> 2 SD of the mean)19. pressure, diabetes mellitus, duration of symptoms andetiology of CHF, basal NYHA class, LVEF, mitral re- Statistical analysis. The differences in continuous
gurgitation and LVEDV were considered, the duration variables between groups were assessed by an analysis of symptoms (< 6 months) emerged as the only inde- of variance (ANOVA/MANOVA); post-hoc compar- pendent predictor both of clinical improvement (odds isons were analyzed by the Scheffé test. Differences in ratio 7.3, confidence interval 19.1-2.7, p < 0.0001) and categorical variables were tested by ␹2 tests. Multivari- left ventricular reverse remodeling process (odds ratio ate analysis was used to evaluate the independent pre- 3.3, confidence interval 8.3-1.3, p = 0.01). C Opasich et al - Carvedilol in elderly HF patients with atrial fibrillation Table I. Comparison between atrial fibrillation and sinus rhythm elderly patients treated and not treated with carvedilol.
ACE = angiotensin-converting enzyme; AT-I = angiotensin I; LVEF = left ventricular ejection fraction. Only significant ␹2 are depict-ed. * digoxin percentage significantly higher in atrial fibrillation patients treated (p = 0.02) and not treated (p = 0.004) with carvedilol;** valvular etiology significantly higher in atrial fibrillation patients treated (p = 0.0001) and not treated (p = 0.0001) with carvedilol;§ ischemic etiology significantly lower (p = 0.0001) in atrial fibrillation patients not treated with carvedilol.
During the follow-up of the patients with atrial fib- carvedilol therapy. Furthermore, conflicting results rillation, 10 of those on carvedilol were rehospitalized emerged by subgroup analyses of the CIBIS II and at least once (25%) as were 15 of those patients not re- MERIT-HF trials regarding the effects of bisoprolol ceiving beta-blocker therapy (60%). The respective and metoprolol in reducing the risk of death and/or hos- numbers for sinus rhythm patients were 31 (25%) and pitalization in CHF patients with atrial fibrillation22-24. 26 (48%). Thus, combining 1-year death and hospital- No clinical investigation provided any information izations, atrial fibrillation patients on carvedilol had a about a possible influence of atrial fibrillation on the re- lower rate of events than did patients not receiving the sponse to beta-blocker therapy in elderly patients with beta-blocker (31 vs 69%, p = 0.003). This reduction in CHF. In this 1-year observational study, carvedilol was event rate is even greater than that seen in the sinus equally effective in improving symptoms and left ven- rhythm patients (41% in carvedilol-treated patients vs tricular systolic function in elderly patients with atrial 56% in patients not given carvedilol, p = 0.0059).
fibrillation or in sinus rhythm, without any adjunctivesign of long-term clinical deterioration (i.e. there wasno change in the dosage of loop diuretics, and there was Discussion
a reduction in the combined endpoint of hospitaliza-tions and death).
The effectiveness of beta-blocker therapy in CHF Considering the older age and the multiple comor- patients with atrial fibrillation is still controversial.
bidities of our patients, the percentage of “clinical im- Similar degrees of clinical and LVEF improvements in provement” found in the subjects with atrial fibrillation response to carvedilol were reported in patients with (near a quarter of survivors) has to be considered par- atrial fibrillation in a retrospective analysis of 45 pa- ticularly high. In our analysis atrial fibrillation per se tients in Arnold’s study20 as well as in the US did not influence the clinical effects of beta-blocker Carvedilol Heart Failure Trials Program17. Moreover, therapy, which exclusively depended, instead, on the in this latter trial, there was a trend (albeit not statisti- duration of the cardiac syndrome. Similarly, the pres- cally significant) toward a reduction in the combined ence of atrial fibrillation in CHF elders receiving endpoint of death and heart failure hospitalization in carvedilol did not reduce the likelihood of developing the carvedilol group. However, when changes in LVEF left ventricular reverse remodeling process, which was, after carvedilol treatment were measured by Schleman once again, inversely related to the duration of heart et al.21, a significant negative correlation was found failure symptoms. Our data confirm the analyses of with the presence of atrial fibrillation, which also was Palazzuoli et al.25 and Konstam et al.26, who clearly associated with hospitalization after initiation of showed in the recent past that left ventricular reverse remodeling may take place in many elderly as well asin younger CHF patients. An expected finding of our observation was that pa- tients with atrial fibrillation, who had a slightly higher mean heart rate at baseline, required higher dosages of carvedilol than those with sinus rhythm specifically for the ventricular response control. It is worth noting,however, that the reductions in heart rate and systolic blood pressure were similar in both groups, irrespective of the dose prescribed at the end of follow-up. Further, unlike controlled clinical trials, only a minority of our patients achieved the “target dose” of 50 mg daily (giv-en in a similar percentage of atrial fibrillation and sinus rhythm patients), and yet effects on the clinical status and left ventricular geometry were evident, suggestingthat even low doses may be effective in elderly patientswith CHF7,8,27,28.
The originality of the present study lies in the com- bination of the two clinical variables such as age > 70 years and atrial fibrillation; its limits are that it is an ob-servational and non-randomized study in a small sam-ple of patients, with few clinical endpoints. Our experi- ence suggests that the beneficial effects of carvedilol on the clinical status and left ventricular geometry and function are independent of cardiac rhythm even in el- derly CHF patients with left ventricular systolic dys- function. While waiting the results of subgroup analy- sis of the SENIORS trial, this information may reassure physicians who operate in the general setting that in- cludes older patients with multiple comorbidities.
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